Integrins, insulin like growth factors, and the skeletal response to load

Abstract

Bone loss during skeletal unloading, whether due to neurotrauma resulting in paralysis or prolonged immobilization due to a variety of medical illnesses, accelerates bone loss. In this review the evidence that skeletal unloading leads to bone loss, at least in part, due to disrupted insulin like growth factor (IGF) signaling, resulting in reduced osteoblast proliferation and differentiation, will be examined. The mechanism underlying this disruption in IGF signaling appears to involve integrins, the expression of which is reduced during skeletal unloading. Integrins play an important, albeit not well defined, role in facilitating signaling not only by IGF but also by other growth factors. However, the interaction between selected integrins such as alphaupsilonbeta3 and beta1 integrins and the IGF receptor are of especial importance with respect to the ability of bone to respond to mechanical load. Disruption of this interaction blocks IGF signaling and results in bone loss.

Fig. 1

IGF signaling pathway. IGF I or II binds to the IGF-I receptor, a heterotetramer comprised of two alpha and two beta subunits. Upon binding of IGF, the receptor undergoes autophosphorylation of critical tyrosine residues, and two major pathways are activated. The first pathway leads to activation of Ras and the MAPK pathway eventuating in the activation of ERK1/2, which can enter the nucleus to induce genes important for proliferation. The second pathway leads to the activation of PI3K resulting in activation of Akt, which exerts anti-apoptotic actions by phosphorylating and so inactivating Bad, a proapoptotic regulator of Bcl-2

Fig. 2

The members of the human integrin superfamily and how they combine to form heterodimeric integrins. At least 18 α subunits and 8 β subunits have been identified in humans, which combine to generate 24 different integrins. Integrin subunits that can bind to each other to form a heterodimer are connected by solid lines

Fig. 3

A model of an integrin lacking the I domain in the α subunit (the typical integrin involved with IGF signaling in bone). The β-propeller domain of the α subunit and the β1 domain of the β subunit form the binding domain for the extracellular ligand, in this case a matrix RGD containing protein such as osteopontin, vitronectin, or fibronectin. Binding of the ligand causes a conformational change in the integrin subunits resulting in separation of the intracellular portions of the tails, enabling binding to a number of proteins to those tails such as FAK and talin that mediate integrin signaling

Fig. 4

Model for IGF/integrin signaling interactions in regulating the skeletal response to load. The IGF-IR forms a complex with αυβ3 integrin that is required for IGF-I activation of the IGF-IR. This complex may be formed via the scaffolding function of FAK/Pyk2 or that of caveolin-1. SHPS-1 may play a role by regulating access of the phosphatase SHP-2 to this complex. Mechanical load increases whereas unloading decreases formation of this complex and so regulates IGF-I responsiveness. Formation of the integrin/IGF-IR complex brings to the IGF-IR non-receptor kinases such as FAK and src family kinases which may activate the IGF-IR independently and/or synergistically with IGF-I. The source of IGF-I may originate from osteocytes and osteoblasts. Production of IGF-I as well as expression and activation of integrins in these cells are stimulated by mechanical load